Linezolid - Tigecycline
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1 Linezolid - Tigecycline Paul M. Tulkens, MD, PhD Cellular and Molecular Pharmacology Louvain Drug Research Institute Catholic University of Louvain, Brussels, Belgium With the support of Wallonie-Bruxelles-International WBI - HUP Cooperation - Bach Mai Hospital 1
2 Dong-A pharmaceuticals and tedizolid: step # WBI - HUP Cooperation - Bach Mai Hospital 2
3 Mode of action: Protein synthesis inhibition: LZD binds to the 23S portion of the ribosomal 50S subunit (the centre of peptidyl transferase activity) no initial complex WBI - HUP Cooperation - Bach Mai Hospital 3
4 RNA interaction Karen L. Leach et al, Molecular Cell (2007) 26, WBI - HUP Cooperation - Bach Mai Hospital 4
5 Spectrum of activity No useful activity against other Gram-negative organisms because of constitutive efflux! WBI - HUP Cooperation - Bach Mai Hospital 5
6 Registered clinical indications Linezolid is often used off-label (endocarditis, osteomyelitis,.) in pace of vancomycin WBI - HUP Cooperation - Bach Mai Hospital 6
7 Linzezolid: mechanism of resistance WBI - HUP Cooperation - Bach Mai Hospital 7
8 Can linzolid induce resistance? WBI - HUP Cooperation - Bach Mai Hospital 8
9 Linzolid can induce resistance Locke et al. Antimicrob Agent Chemother 2009;53: WBI - HUP Cooperation - Bach Mai Hospital 9
10 Linezolid pharmacokinetics WBI - HUP Cooperation - Bach Mai Hospital 10
11 Linezolid human pharmacokinetics Oral therapeutic doses (600mg linezolid q12h for 21 days) Linezolid Tedizolid MIC 90 MIC 90 Muñoz et al. ECCMID 2010; P WBI - HUP Cooperation - Bach Mai Hospital Flanagan SD, et al. Pharmacotherapy 2014;34(3): Munoz KA, et al. ECCMID Poster
12 Linezolid human pharmacokinetics: adults Oral therapeutic doses (600mg linezolid q12h) Tedizolid MIC WBI - HUP Cooperation - Bach Mai Hospital Flanagan SD, et al. Pharmacotherapy 2014;34(3): Munoz KA, et al. ECCMID Poster
13 Linezolid human pharmacokinetics: children MIC WBI - HUP Cooperation - Bach Mai Hospital Flanagan SD, et al. Pharmacotherapy 2014;34(3): Munoz KA, et al. ECCMID Poster
14 Pharmacokinetics/Pharmacodynamics WBI - HUP Cooperation - Bach Mai Hospital 14
15 Concentration PK parameters governing the activity of antibiotics C max C max / MIC f T > MIC AUC 24h / MIC f T > MIC MIC Time (h) WBI - HUP Cooperation - Bach Mai Hospital 15
16 Tedizolid vs linezolid: human pharmacokinetics drug dosage C max (mg/l) apparent t 1/2 (h) linezolid IV mg Q12 h Clearance (ml/min) Total AUC 24h (mg h/l) 15.1 ± ± ± ± Zyvox US Prescription Information (multiple doses) WBI - HUP Cooperation - Bach Mai Hospital 16
17 Linezolid adverse effects Drug interactions: cytochrome P450: no special effect antibiotics: rifampin causes a 21 % in LZD serum levels Monoamine oxidase inhibition (reversible, nonselective inhibitor): adrenergic and serotonergic agents (PRECAUTIONS) Myelosuppression (including anemia, leukopenia, pancytopenia and thrombocytopenia) (WARNING) Hypoglycemia Lactic acidosis (PRECAUTION Immediate medical attention) Peripheral and optic neuropathy (>28 days) Convulsions Zyvox US Prescribing Information, WBI - HUP Cooperation - Bach Mai Hospital 17
18 Linezolid adverse effects Drug interactions: cytochrome P450: no special effect antibiotics: rifampin causes a 21 % in LZD serum levels Monoamine oxidase inhibition (reversible, nonselective inhibitor): adrenergic and serotonergic agents (PRECAUTIONS) Myelosuppression (including anemia, leukopenia, pancytopenia and thrombocytopenia) (WARNING) Hypoglycemia Lactic acidosis (PRECAUTION Immediate medical attention) Peripheral and optic neuropathy (>28 days) Convulsions Zyvox US Prescribing Information, WBI - HUP Cooperation - Bach Mai Hospital 18
19 Monoamine oxidase (MAO) substrate specificity Consequences of MAO-A Inhibition Serotonin Syndrome Hypertensive crisis MAO-A Serotonin Noradrenaline Adrenaline Octopamine Dopamine Tyramine a Tryptamine Kynuramine 3-methoxytyramine MAO-B Benzylamine Phenylethylamine N-phenylamine Octylamine N-acetylputrescine Milacemide N-methyl-4-phenyl- 1,2,3,6- tetrahydropyridine a MAO-A is the predominate form for oxidation of tyramine Elmer & Bertoni. Expert Opin Pharmacother 2008;9: WBI - HUP Cooperation - Bach Mai Hospital 19
20 Is serotonergic syndrome an important problem? Boyer & Shannonl New Eng J Med 2005;352: WBI - HUP Cooperation - Bach Mai Hospital 20
21 This is what we tell the pharmacists in Belgium WBI - HUP Cooperation - Bach Mai Hospital 21
22 Linezolid contraindications Monoamine oxidase inhibitors Drugs that elevate blood pressure Serotonergic drugs Precaution Tyramine-containing food WBI - HUP Cooperation - Bach Mai Hospital 22
23 Linezolid adverse effects Drug interactions: cytochrome P450: no special effect antibiotics: rifampin causes a 21 % in LZD serum levels Monoamine oxidase inhibition (reversible, nonselective inhibitor): adrenergic and serotonergic agents (PRECAUTIONS) Myelosuppression (including anemia, leukopenia, pancytopenia and thrombocytopenia) (WARNING) Hypoglycemia Lactic acidosis (PRECAUTION Immediate medical attention) Peripheral and optic neuropathy (>28 days) Convulsions Zyvox US Prescribing Information, WBI - HUP Cooperation - Bach Mai Hospital 23
24 Thrombocytopenia caused by linezolid may be more frequent than previously thought Minson et al. Pharmacother 2010;30: WBI - HUP Cooperation - Bach Mai Hospital 24
25 Cellular models -HL-60 (Human promyelocytic leukemia cells) -THP1 (Human monocytic cell line) WBI - HUP Cooperation - Bach Mai Hospital 25
26 Linezolid-induced thombocytopenia is indeed frequent... Patients with thrombocytopenia no yes grade 1-2 grade (87.2%) 64 (12.8%) 38 (7.6%) 26 (5.2%) grade 1: x 10 3 /mm 3 ; grade 2: x 10 3 /mm 3 ; grade 3: x 10 3 /mm 3 ; grade 4: < 20 x 10 3 /mm 3. Minson et al. Pharmacother 2010;30: WBI - HUP Cooperation - Bach Mai Hospital 26
27 ...and related to initial low platelet levels Patients with thrombocytopenia no yes grade 1-2 grade (87.2%) 64 (12.8%) 38 (7.6%) 26 (5.2%) grade 1: x 10 3 /mm 3 ; grade 2: x 10 3 /mm 3 ; grade 3: x 10 3 /mm 3 ; grade 4: < 20 x 10 3 /mm 3. Minson et al. Pharmacotherapy 2010;30: Minson et al. Pharmacother 2010;30: WBI - HUP Cooperation - Bach Mai Hospital 27
28 ...and aggravated by renal failure Wu et al. Clin Infect Dis 2006;42: WBI - HUP Cooperation - Bach Mai Hospital 28
29 Linezolid adverse effects Drug interactions: cytochrome P450: no special effect antibiotics: rifampin causes a 21 % in LZD serum levels Monoamine oxidase inhibition (reversible, nonselective inhibitor): adrenergic and serotonergic agents (PRECAUTIONS) Myelosuppression (including anemia, leukopenia, pancytopenia and thrombocytopenia) (WARNING) Hypoglycemia Lactic acidosis (PRECAUTION Immediate medical attention) Peripheral and optic neuropathy (>28 days) Convulsions Zyvox US Prescribing Information, WBI - HUP Cooperation - Bach Mai Hospital 29
30 Mitochondrial RNA interaction Karen L. Leach et al, Molecular Cell (2007) 26, WBI - HUP Cooperation - Bach Mai Hospital 30
31 Cytox I expression in cells exposed to linezolid incubation with drug washout hours hours 120 cytochrome c oxidase subunit I expression (% of control) LZD 15mg/L LZD hours of incubation hours post washing inhibition time -dependent, effect fully reversibly WBI - HUP Cooperation - Bach Mai Hospital 31
32 WBI - HUP Cooperation - Bach Mai Hospital 32 When do we use linezolid? as substitute to vancomycin when patient leaves the hospital (oral form) intolerance MICs of vancomycin > 2 and no other alternative with close control of the patient (weakly) for thrombocytopenia and anemia lactic acidosis risk of serotoninegic syndrome
33 Tygecycline (in very short) WBI - HUP Cooperation - Bach Mai Hospital 33
34 WBI - HUP Cooperation - Bach Mai Hospital 34 Tigecycline: historical landmarks Disvovery of glycylcyclines as a novel class of antibiotics In vitro and in vivo antibacterial activities of the glycylcyclines, a new class of semisynthetic tetracyclines. Testa et al. Antimicrob Agents Chemother : Demonstration of the spectrm of activity and candidate selection In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (GAR-936). Petersen et al. (1999) Antimicrob Agents Chemother. 43:
35 WBI - HUP Cooperation - Bach Mai Hospital 35 Tigecycline: chemical structure minocycline t-butyl H 3 C H 3 C CH 3 glycyl- H N O C N H H 3 C NH OH CH 3 O H 3 C CH 3 NH OH OH O OH C NH 2 O
36 WBI - HUP Cooperation - Bach Mai Hospital 36 Mode of action of tigecycline tigecycline tetracycline minocycline same binding site as tetracyclines in ribosome 16S RNA; additional interaction site Unaffected by resistance due to - ribosomal protection - Tet efflux pumps; But remains susceptible to broad spectrum efflux pumps of Gram(-) (MexXY in P. aeruginosa) Olson et al., AAC (2006) 50:
37 WBI - HUP Cooperation - Bach Mai Hospital 37 Tetra- and glycyl-cyclines: activity and resistance species phenotype tetracycline minocycline tigecycline E. coli susceptible Efflux (Tet) > Ribosomal protection > 32 > S. aureus susceptible Efflux (Tet) > Ribosomal protection > Petersen et al., AAC (1999) 43:738-44
38 Tigecycline: registered indications (US) WBI - HUP Cooperation - Bach Mai Hospital 38
39 Tigecycline: known clinical failures WBI - HUP Cooperation - Bach Mai Hospital 39
40 Tigecycline: known clinical failures WBI - HUP Cooperation - Bach Mai Hospital 40
41 Tigecycline: pharmacokinetics WBI - HUP Cooperation - Bach Mai Hospital 41 tissue AUC 24h (mg.h/l) serum/tissue AUC ratio bile Single dose: 100 mg bladder colon lung bone synovial fluid CSF mg + 6x50 mg q12h ELF alveolar MΦ Rodvold, JAntimicrob Chemother (2006) 58: Conte et al., Int J Antimicrob Agents (2005) 25:523-9
42 WBI - HUP Cooperation - Bach Mai Hospital 42 PK/PD of tigecycline animal models Mouse thigh - S. pneumoniae Efficacy for AUC 24h /MIC of 1-5 (free fraction) ~ (total conc.) van Ogtrop et al., AAC (2000) 44:943-9
43 WBI - HUP Cooperation - Bach Mai Hospital 43 Tigecycline EUCAST breakpoints cumulative percentage of strains tigecycline MIC (mg/l) But will this last? (T.E.S.T. will tell but TK reports MIC 90 at 0.75 In 2008) Denis et al., AAC (2006) 50:2680-5
44 WBI - HUP Cooperation - Bach Mai Hospital 44 Could we use higher doses than recommended? The recommended dosage regimen for TYGACIL is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous infusions of TYGACIL should be administered over approximately 30 to 60 minutes every 12 hours.
45 Could we use higher doses than recommended? WBI - HUP Cooperation - Bach Mai Hospital 45
46 WBI - HUP Cooperation - Bach Mai Hospital 46 When do we use tigecycline? skin and skin structures / abdominal infections with multi-resistant organisms susceptible to tigecyline Because of increased mortality compared to other antibiotics, tigecycline uts only be used when alternatives are not available
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